title: Smad7 is required for the development and function of the heart.
abstract: Transforming growth factor-beta (TGF-beta) family members, including TGF-betas, activins, and bone morphogenetic proteins, exert diverse biological activities in cell proliferation, differentiation, apoptosis, embryonic development, and many other processes. These effects are largely mediated by Smad proteins. Smad7 is a negative regulator for the signaling of TGF-beta family members. Dysregulation of Smad7 is associated with pathogenesis of a variety of human diseases. However, the in vivo physiological roles of Smad7 have not been elucidated due to the lack of a mouse model with significant loss of Smad7 function. Here we report generation and initial characterization of Smad7 mutant mice with targeted deletion of the indispensable MH2 domain. The majority of Smad7 mutant mice died in utero due to multiple defects in cardiovascular development, including ventricular septal defect and non-compaction, as well as outflow tract malformation. The surviving adult Smad7 mutant mice had impaired cardiac functions and severe arrhythmia. Further analyses suggest that Smad2/3 phosphorylation was elevated in atrioventricular cushion in the heart of Smad7 mutant mice, accompanied by increased apoptosis in this region. Taken together, these observations pinpoint an important role of Smad7 in the development and function of the mouse heart in vivo.
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Kuang
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Zou
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Guixue
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Ting
authors.initials: T
authors.lastname: Jin
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093. Electronic address: wshou@iupui.edu.
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.affiliation: Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093. Electronic address: ychen3@sibs.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta